An Expedient Route to Montanine-Type Amaryllidaceae Alkaloids

Sep 10, 2008 - The first total syntheses of (−)-brunsvigine (1) and (−)-manthine (2) were accomplished in 10 and 18 steps, respectively. (−)-Qui...
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An Expedient Route to Montanine-Type Amaryllidaceae Alkaloids: Total Syntheses of (-)-Brunsvigine and (-)-Manthine An-Wei Hong, Tsung-Hui Cheng, Vellingiri Raghukumar, and Chin-Kang Sha* Department of Chemistry, National Tsing Hua UniVersity, Hsinchu 300, Taiwan, ROC [email protected] ReceiVed June 2, 2008

The first total syntheses of (-)-brunsvigine (1) and (-)-manthine (2) were accomplished in 10 and 18 steps, respectively. (-)-Quinic acid was converted to enone 12 in five steps. Iodination of enone 12 followed by stereoselective reduction yielded R-iodo allylic alcohol 16. Conversion of alcohol 16 into Weinreb amide 11 followed by anionic cyclization gave bicyclic enone 10. Stereoselective reduction of enone 10 and subsequent protection afforded pivaloate 9. Grignard addition of 8 to 9 and detosylation afforded amine derivative 19. Pictet-Spengler cyclization of 19 with Eschenmoser′s salt and subsequent hydrolysis gave enantiomerically pure (-)-brunsvigine (1). For the total synthesis of (-)-manthine (2), the key intermediate 7 was hydrolyzed to diol 21. Conversion of 21 into 22 followed by regioselective cleavage with DIBAL furnished alcohol 25. Alcohol 25 was converted to the corresponding triflate 26, which on treatment with CsOAc and 18-crown-6 gave stereoinverted acetate 27. Hydrolysis of acetate 27 followed by methylation afforded compound 29. Detosylation of 29 afforded amine derivative 30. Pictet-Spengler cyclization of 30 followed by debenzylation gave alcohol 33. Finally, methylation of alcohol 33 afforded (-)-manthine (2).

Introduction (-)-Brunsvigine and (-)-manthine, which are representative members of montanine-type Amaryllidaceae alkaloids 1-6,1-3 incorporate an intriguing pentacyclic 5,11-methanomorphanthridine as the core skeleton. These alkaloids differ only in the stereochemistry of the C2 and C3 oxygen substituents in the E ring (Figure 1).4 When Wildman and co-workers initiated the investigation of Amaryllidaceae alkaloids in 1955,5 they isolated (-)-manthine (2) from Haemathus species and (-)-brunsvigine (1) from BrunsVigia cooperi and BrunsVigia radulosa Herp.1,2 These montanine-type alkaloids possess important biological (1) Dry, L. J.; Poynton, M. E.; Thompson, M. E.; Warren, F. L. J. Chem. Soc. 1958, 4701. (2) Inubushi, Y.; Fales, H. M.; Warnhoff, E. W.; Wildman, W. C. J. Org. Chem. 1960, 25, 2153. (3) Wildman, W. C.; Brown, C. L. J. Am. Chem. Soc. 1968, 90, 6439. (4) (a) Martin, S. F. The Amaryllidaceae Alkaloids. In The Alkaloids; Brossi, A., Ed.; Academic Press: San Diego, CA, 1987; Vol. 30, p 252. (b) Lewis, J. R. Nat. Prod. Rep. 1993, 10, 291. (c) Viladomat, F.; Bastida, J.; Codina, C.; Campbell, W. E.; Mathee, S. Phytochemistry 1995, 40, 307. (5) Wildman, W. C.; Kaufman, C. J. J. Am. Chem. Soc. 1955, 77, 1248.

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FIGURE 1. Structure of montanine-type Amaryllidaceae alkaloids.

activities including anxiolytic, antidepressant, and anticonvulsant-type effects.6,7 In conjunction with these activities, the unique pentacyclic structure of these alkaloids has stimulated considerable interest from the synthetic community. 10.1021/jo801089y CCC: $40.75  2008 American Chemical Society Published on Web 09/10/2008

Montanine-Type Amaryllidaceae Alkaloids SCHEME 1.

Retrosynthesis of (-)-Brunsvigine (1) and (-)-Manthine (2)

Since Overman reported the first total synthesis of (()pancracine,8 several total syntheses of natural products in this family have been published. In a series of accounts,9 Hoshino and co-workers reported two elegant schemes to construct the 5,11-methanomorphanthridine ring system, resulting in preparation of (()-montanine, (()-coccinine, (()-pancracine, (()brunsvigine, and (()-O-acetylmontanine. In 1993, Overman and Shim reported the first asymmetric total synthesis of (-)pancracine10 employing an aza-Cope-Mannich reaction as the key step. Weinreb et al. reported an enantioselective total syntheses of (-)-coccinine and (-)-pancracine with a formal total synthesis of (-)-brunsvigine.11 Ishibashi and co-workers reported a clever total synthesis of (()-pancracine12 employing radical cyclization as the key step. Pandey′s group utilized a 1,3-dipolar cycloaddition of a nonstabilized azomethine ylide to construct the 5,11-methanomorphanthridine ring system.13 Several formal total syntheses of various members of alkaloids of the montanine type are reported, and the syntheses of antipodes of the natural products, (+)-coccinine14 and (+)brunsvigine,15 have also been described. Although a massive synthetic effort has been directed toward almost all members of the montanine-type alkaloids, there has been no report other than our own16 of the total syntheses of (-)-brunsvigine (1) and (-)-manthine (2). Herein, we report our total syntheses of enantiomerically pure (-)-brunsvigine (1) and (-)-manthine (2). (6) Southon, I. W.; Buckinghham, J. Dictionary of Alkaloids; Chapman & Hall: New York, 1989; pp 229-735. (7) Schu¨rmann da Silva, A. F.; de Andrade, J. P.; Bevilaqua, L. R. M.; da Souza, M. M.; Izquierdo, I.; Henriques, A. T.; Zuanazzi, J. A. S. Pharmacol., Biochem. BehaV. 2006, 85, 148. (8) Overman, L. E.; Shim, J. J. Org. Chem. 1991, 56, 5005. (9) (a) Ishizaki, M.; Hoshino, O.; Iitaka, Y. Tetrahedron Lett. 1991, 32, 7079. (b) Ishizaki, M.; Hoshino, O. J. Org. Chem. 1992, 57, 7285. (c) Ishizaki, M.; Kurihara, K.-I.; Tanazawa, E.; Hoshino, O. J. Chem. Soc., Perkin Trans. 1 1993, 101. (10) Overman, L. E.; Shim, J. J. Org. Chem. 1993, 58, 4662. (11) (a) Jin, J.; Weinreb, S. M. J. Am. Chem. Soc. 1997, 119, 2050. (b) Jin, J.; Weinreb, S. M. J. Am. Chem. Soc. 1997, 119, 5773. (12) Ikeda, M.; Hamada, M.; Yamashita, T.; Ikegami, F.; Sato, T.; Ishibashi, H. Synlett 1998, 1246. (13) Pandey, G.; Banerjee, P.; Kumar, R.; Puranik, V. G. Org. Lett. 2005, 7, 3713. (14) Pearson, W. H.; Lian, B. W. Angew. Chem., Int. Ed. 1998, 37, 1724. (15) Banwell, M. G.; Kokas, O. J.; Willis, A. C. Org. Lett. 2005, 9, 3503. (16) A preliminary communication of this work has been published: Sha, C.-K.; Hong, A.-W.; Huang, C.-M. Org. Lett. 2001, 3, 2177.

We envisaged that the unique 5,11-methanomorphanthridine ring system of (-)-brunsvigine (1) and (-)-manthine (2) might be established by a Pictet-Spengler reaction (Scheme 1). The necessary variation at C2 and C3 stereocenters would be accessible by taking advantage of synthetic transformations. Key intermediate 7 would be generated from a coupling of Grignard 8 and compound 9. Compound 9 would be obtained from reduction and esterification of enone 10. Enone 10 might be prepared from Weinreb amide 11 via an anionic cyclization. Weinreb amide 11 could be obtained from commercially available (-)-quinic acid through a sequence of transformations of functional groups. Results and Discussion Our synthetic efforts began with commercially available (-)quinic acid. The requisite chiral enone 12 was prepared from (-)-quinic acid by adapting a literature procedure.17 Iodination of enone 12 was accomplished with Johnson′s procedure18 to provide iodoenone 13. Compound 13 upon treatment with NaBH4 in the presence of CeCl3 · 7H2O19 afforded a mixture of epimers 14 and 16, which were separated by column chromatography. As β-isomer 16 was used in the synthesis, the unwanted R-isomer 14 was consequently converted into the required β-isomer via a Mitsunobu reaction. Treatment of 14 with p-nitrobenzoic acid in the presence of triphenylphosphine and diethyl azodicarboxylate gave 15. Compound 15 was hydrolyzed with NaOH in MeOH to give compound 16. Introduction of the Weinreb amide side chain to compound 16 afforded compound 11. Anionic cyclization of Weinreb amide 11 in the presence of n-BuLi thus furnished the desired bicyclic enone 10 (Scheme 2). Total Synthesis of (-)-Brunsvigine (1). Stereoselective reduction of enone 10 with NaBH4/CeCl3 · 7H2O gave the corresponding alcohol 18, which was then converted to pivaloate (17) (a) Elliott, J. D.; Hetmanski, M.; Stoodley, R. J. J. Chem. Soc., Perkin Trans. 1 1981, 1782. (b) Rohloff, J. C.; Kent, K. M.; Postich, M. J.; Becker, M. W.; Chapman, H. H.; Kelley, D. E.; Lew, W.; Louie, M. S.; McGee, L. R.; Prisbe, E. J.; Schultze, L. M.; Yu, R. H.; Zhang, L. J. Org. Chem. 1998, 63, 4545. (18) Johnson, C. R.; Adams, J. P.; Braun, M. P.; Senanyake, C. B. W.; Wovkulich, P. M.; Uskokovic, M. R. Tetrahedron Lett. 1992, 33, 917. (19) Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226.

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Hong et al. SCHEME 2.

Synthesis of Chiral Azabicyclic Enone 10

SCHEME 3.

Total Synthesis of (-)-Brunsvigine

9. The stereochemistry of 9 was unambiguously assigned through a single-crystal X-ray analysis.20 A CuI-mediated SN2 reaction of 9 with 3,4-(methylenedioxy)phenylmagnesium bromide (8) afforded key intermediate 721 in 76% yield. Detosylation of 7 was executed on titration with sodium naphthalide at -78 °C to produce amine 19. To complete the synthesis, we treated amine 19 with dimethylmethyleneimmonium iodide22 and subsequently hy(20) X-ray data of compounds 16 and 1a are presented in the Supporting Information. (21) Tseng, C. C.; Yen, S.-J.; Goering, H. L. J. Org. Chem. 1986, 51, 2892. (22) Clark, R. C.; Warren, R. L.; Pachler, K. G. R. Tetrahedron 1975, 31, 1855.

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drolyzed the ketal group to yield (-)-brunsvigine (1) (Scheme 3) with an overall yield of 12% from chiral enone 12. The specific rotation [R]23D) -76.3 (c 1.02, EtOH; lit. [R]20D) -76.6 (c 1.0, EtOH)), melting point, and spectral data of 1 agree with literature data.1,2 To confirm the structure, we converted the synthetic (-)-brunsvigine (1) to the stable crystalline diacetate 1a. Structure of 1a was determined by single-crystal X-ray analysis.20 Total Synthesis of (-)-Manthine (2). After having success with the total synthesis of (-)-brunsvigine (1), we turned our attention to the synthesis of (-)-manthine (2). We began the synthesis with key intermediate 7 (Scheme 4). However, in this

Montanine-Type Amaryllidaceae Alkaloids SCHEME 4.

Total Synthesis of (-)-Manthine

synthetic route, we had to find a suitable method to invert the C-O bond in the C3 stereocenter. Our next phase of synthesis accordingly began with hydrolysis of the acetonide moiety in 7 to furnish diol 21. Treatment of diol 21 with dimethoxymethylbenzene and camphorsulfonic acid gave intermediate 22. Compound 22 was not isolated and immediately subjected to regioselective cleavage with diisobutylaluminum hydride (DIBAL)9b to give alcohol 25. This reaction presumably proceeded through complexation of DIBAL with an oxygen atom of the acetal unit in 22. Since the axial oxygen of 22 is more hindered, the DIBAL may prefer to coordinate with the less hindered equatorial oxygen to form

the complex 23. Reductive cleavage of 23f24 led to formation of 3-hydroxy product 25 exclusively. Exposure of 25 to trifluoromethanesulfonic anhydride and pyridine in dichloromethane afforded the corresponding triflate 26. Compound 26 was efficiently transformed to the corresponding stereoinverted acetate 27 using cesium acetate and 18crown-6 in toluene.23 Hydrolysis of 27 with sodium methoxide in methanol gave compound 28. Methylation of compound 28 afforded compound 29. Detosylation of 29 with sodium and (23) (a) Shimizu, T.; Hiranuma, S.; Nakata, T. Tetrahedron Lett. 1996, 37, 6145. (b) Hiranuma, S.; Shimizu, T.; Nakata, T.; Kajimoto, T.; Wong, C.-H. Tetrahedron Lett. 1995, 36, 8247.

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naphthalene in DME at –78 °C gave amine derivative 30.24 Treatment of 30 at rt with aqueous formaldehyde and methanolic HCl generated iminium intermediate 31, which readily underwent Pictet-Spengler cyclization11b,12,25 to give 32. Deprotection of the benzyl group in 32 followed by methylation finally afforded (-)-manthine (2). The specific rotation [R]25.9D ) -78.4 (c 0.50, CHCl3; lit. [R]25.9D ) -80.0 (c 0.51, CHCl3)), melting point, and spectral data of the synthetic (-)-manthine (2) agree satisfactorily with the literature data.3,9 In summary, we have developed a concise and expedient route toward the total syntheses of (-)-brunsvigine (1) and (-)manthine (2). Our syntheses feature an efficient and stereocontrolled construction of bicyclic enone 10 employing anionic cyclization. A sequence of synthetic transformations on bicyclic enone 10 established the pivotal framework 7. Pictet-Spengler cyclization was strategically applied to construct the 5,11methanomorphanthridine ring system that led to the first total syntheses of (-)-brunsvigine (1) and (-)-manthine (2). An extension and further application of this method to the total synthesis of other alkaloids are under active investigation in our laboratory. Experimental Section (1S,13S,15R,19S)-17,17-Dimethyl-5,7,16,18-tetraoxa-12-azahexacyclo[10.9.1.02,10.04,8.013,21.015,19]docosa-2,4(8),9,20-tetraene (20). To a solution of 19 (75.2 mg, 0.239 mmol) in dry DMF (6 mL) was added dimethylmethyleneimmonium iodide (812 mg, 4.39 mmol). The reaction mixture was stirred at 90-100 °C for 6 h. Upon cooling to 0 °C, the reaction mixture was quenched with water (2 mL) and basified on addition of aqueous NH3 (3 mL). The aqueous phase was extracted with chloroform (10 mL × 3). The combined extract was washed with brine (5 mL) and dried over Na2SO4. Concentration and chromatography on a silica gel column (methanol/ CHCl3 1:30) gave 20 (48 mg, 62%). Data for 20: IR (neat) νmax 2983, 2936, 2882, 1503, 1482, 1372 cm-1; 1H NMR (400 MHz, CDCl3) δ 6.54 (s, 1H), 6.45 (s, 1H), 5.88 and 5.85 (AB quartet, 2H, J ) 1.4 Hz), 5.69 (dd, 1H, J ) 2.2, 2.2 Hz), 4.48-4.43 (m, 1H), 4.33 and 3.77 (AB quartet, 2H, J ) 17.0 Hz), 4.26 (ddd, 1H, J ) 11.6, 5.6, 5.6 Hz), 3.33-3.00 (m, 1H), 3.11 (dd, 1H, J ) 10.8, 2.0 Hz), 3.08-3.03 (br s, 1H), 3.04 (d, 1H, J ) 10.8 Hz), 2.28 (ddd, 1H, J ) 11.6, 5.6, 5.6 Hz), 1.46 (s, 3H), 1.34 (s, 3H), 1.32 (ddd, 1H, J ) 11.6, 11.6, 11.6 Hz); 13C NMR (100 MHz, CDCl3) δ 155.5 (C), 146.7 (C), 146.0 (C), 132.1 (C), 124.4 (C), 112.2 (CH), 109.4 (C), 107.1 (CH), 106.7 (CH), 100.7 (CH2), 73.6 (CH), 71.6 (CH), 62.0 (CH), 60.7 (CH2), 55.0 (CH2), 45.2 (CH), 33.0 (CH2), 27.7 (CH3), 25.1 (CH3); MS (EI) m/z 327 (M+, 100), 312 (32), 252 (65), 223 (21), 212 (19); HRMS (EI) m/z calcd for C19H21 N O4 327.1470, found 327.1472; [R]18.8D ) -83.5 (c 1.33, CHCl3). (-)-Brunsvigine (1). To a solution of 20 (56.0 mg, 0.171 mmol) in anhydrous MeOH (2 mL) was added concd HCl (0.20 mL, 2.40 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min and then warmed to rt. After stirring for an additional 2 h, the mixture was cooled to 0 °C, then quenched with water (2 mL) and extracted with chloroform (30 mL × 2). The combined organic layer was washed with brine (15 mL) and dried over Na2SO4. Concentration gave crude product 1. Recrystallization from ethyl acetate/n-hexane (2:1) gave compound 1 as a colorless crystal (40 mg, 81%): mp 239-241 °C (lit.1,2 243 °C); IR (neat) νmax 3328, 2964, 2876, 1485, 1337, 1236 cm-1; 1H NMR (600 MHz, CDCl3) δ 6.55 (s, 1H), 6.47 (s, 1H), 5.89 (d, 1H, J ) 1.4 Hz), 5.87 (d, 1H, J ) 1.4 Hz), 5.76-5.75 (m, 1H), 4.36 (d, 1H, J ) 16.6 Hz), 4.13-4.12 (m, 1H), 3.87 (d, 1H, J ) 16.5 Hz), 3.68-3.64 (m, (24) Sungchul, J.; Gortler, L. B.; Waring, A.; Battisti, A.; Bank, S.; Clossen, W. D.; Wriede, P. J. Am. Chem. Soc. 1967, 89, 5311. (25) Keck, G. E.; Webb, R. R., II. J. Am. Chem. Soc. 1981, 103, 3173.

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1H), 3.34 (br s, 1H), 3.26-3.24 (m, 1H), 3.18-3.16 (m, 1H), 3.07 (d, 1H, J ) 11.1 Hz), 2.25-2.22 (m, 1H), 1.58-1.53 (m, 1H); 13C NMR (150 MHz, MeOD/CDCl3) δ 153.2, 148.5, 147.8, 132.8, 124.4, 118.1, 108.4, 107.8, 102.2, 69.6, 67.0, 64.7, 61.0, 56.3, 46.4, 32.7; MS (EI) m/z 287 (M+, 100), 269 (41), 243 (18), 223 (23), 199 (57), 185 (44), 128 (30), 115 (33); HRMS (EI) m/z calcd for C16H17 N O4 287.1158, found 287.1151; [R]20D ) -76.3 (c 1.02, EtOH). (1S,13S,15R,16S)-15-(Methylcarbonyloxy)-5,7-dioxa-12-azapentacyclo[10.6.1.02,10.04,8.013,18]nonadeca-2(10),3,8,17-tetraen-16-yl acetate (1a). To a solution of (-)-brunsvigine (1) (9.9 mg, 0.0347 mmol) and 4-(dimethylamino)pyridine (DMAP) (2.0 mg, 0.0164 mmol) in dry pyridine (2 mL) was added acetic anhydride (25.0 mg, 0.208 mmol) at rt with stirring for 17 h. Concentration and chromatography on a silica gel column (methanol/chloroform) gave compound 1a (10 mg, 78%). Data for 1a: mp 184-185 °C (lit. 184 °C); IR (neat) νmax 2938, 2880,1741, 1504, 1480, 1249 cm-1; 1H NMR (400 MHz, CDCl ) δ 6.51 (s, 1H), 6.45 (s, 1H), 5.88 and 3 5.85 (AB quartet, 2H, J ) 1.2 Hz), 5.54-5.52 (m, 1H), 5.45 (dd, 1H, J ) 4.0, 4.0 Hz), 4.93 (ddd, 1H, J ) 12.0, 4.0, 4.0 Hz), 4.30 and 3.80 (AB quartet, 2H, J ) 16.8 Hz), 3.32-3.25 (br s, 1H), 3.27 (br s, 1H), 3.08 and 3.04 (AB quartet, 2H, J ) 17.0 Hz), 2.16-2.10 (m, 1H), 2.07 (s, 3H), 1.99 (s, 3H), 1.71 (ddd, 1H, J ) 12.0, 12.0, 12.0 Hz); 13C NMR (100 MHz, CDCl3) δ 170.4, 170.0, 156.5, 147.0, 146.1, 131.4, 124.5, 112.1, 107.5, 106.9, 100.8, 68.8, 66.1, 63.0, 61.2, 56.0, 45.4, 30.2, 21.0, 20.9; MS (EI) m/z 371 (M+, 32), 312 (67), 252 (100), 223 (32); HRMS (EI) m/z calcd for C20H21NO6 371.1369, found 371.1372. (3S,5S,6R,7aS)-3-(1,3-Benzodioxol-5-yl)-1-[(4-methylphenyl)sulfonyl]-2,3,5,6,7,7a-hexahydro-1H-6-indolediol (21). To a solution of 7 (302 mg, 0.644 mmol) in MeOH/ THF (5 mL/5 mL) was added concd HCl (0.53 mL) at 0 °C with stirring for 10 min. The mixture was warmed to rt and stirred for an additional 2 h. The reaction was then quenched with K2CO3 (3 N, 5 mL) and extracted with dichloromethane (30 mL × 3). The combined organic extract was washed with brine (15 mL) and dried over Na2SO4. Concentration and chromatography on a silica gel column (ethyl acetate/nhexane 2:1) gave 21 as a white solid (275 mg, 99%). Data for 21: mp 166.5-166.7 °C; IR (neat) νmax 3411, 2891, 1504, 1491, 1342 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.59 (d, 2H, J ) 8.0 Hz), 7.20 (d, 2H, J ) 8.0 Hz), 6.51 (d, 1H, J ) 8.0 Hz), 6.29 (dd, 1H, J ) 8.0, 1.6 Hz), 6.19 (d, 1H, J ) 1.6 Hz), 5.86 (s, 2H), 5.77 (br s, 1H), 4.12 (br s, 1H), 3.89 (dd, 1H, J ) 10.4, 7.2 Hz), 3.83-3.78 (m, 1H), 3.76-3.68 (br s, 1H), 3.64-3.55 (br s, 1H), 3.26 (dd, 1H, J ) 10.4, 4.4 Hz), 3.13 (br s, 1H), 2.90 (br s, 1H), 2.64-2.57 (m, 1H), 2.38 (s, 3H), 1.79 (ddd, 1H, J ) 11.6, 11.6, 11.6 Hz); 13C NMR (100 MHz, CDCl3) δ 147.8 (C), 146.4 (C), 145.2 (C), 143.9 (C), 134.9 (C), 132.9 (C), 129.6 (CH), 127.6 (CH), 123.3 (CH), 120.0 (CH), 108.2 (CH), 107.1 (CH), 101.0 (CH2), 67.6 (CH), 65.0 (CH), 59.0 (CH), 55.9 (CH2), 46.0 (CH), 33.3 (CH2), 21.4 (CH3); MS (EI) m/z 429 (M+, 34), 411 (12), 385 (67), 230 (32), 201 (41), 135 (52), 91 (100); HRMS (EI) m/z calcd for C20H21NO6S 371.1369, found 371.1372; [R]21.6D ) +90.4 (c 1.04, CHCl3). (3S,5S,6R,7aS)-3-(1,3-Benzodioxol-5-yl)-5-(benzyloxy)-1-[(4methylphenyl)sulfonyl)]-2,3,5,6,7,7a-hexahydro-1H-6-indolol (25). To a solution of diol 21 (275 mg, 0.641 mmol) in anhydrous dichloromethane (15 mL) were added camphorsulfonic acid (15.0 mg, 0.065 mmol) and dimethoxymethylbenzene (0.19 mL, 1.28 mmol) at rt with stirring for 1 h. The mixture was then cooled to -78 °C. DIBAL (1.0 M solution in toluene, 6.40 mL, 6.40 mmol) was added dropwise via a syringe. The reaction mixture was stirred for an additional 40 min and then warmed to rt. The reaction mixture was quenched with water (5 mL). Subsequent addition of dichloromethane (13 mL) produced a white gel suspension. The resulting mixture was filtered through Celite; the filtrate was dried over Na2SO4. Concentration and chromatography on a silica gel column (ethyl acetate/n-hexane 1:1) gave 25 as a colorless oil (316 mg, 95%). Data for 25: IR (neat) νmax 3542, 2890, 1504, 1490, 1346, 1160 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.61 (d, 2H, J ) 8.0

Montanine-Type Amaryllidaceae Alkaloids Hz), 7.35-7.25 (m, 5H), 7.22 (d, 2H, J ) 8.0 Hz), 6.55 (d, 1H, J ) 8.0 Hz), 6.32 (dd, 1H, J ) 8.0, 2.0 Hz), 6.22 (d, 1H, J ) 2.0 Hz), 5.88 (s, 2H), 5.76-5.73 (m, 1H), 4.70 and 4.59 (AB quartet, 2H, J ) 11.4 Hz), 3.91-3.88 (m, 1H), 3.90 (dd, 1H, J ) 10.6, 7.2 Hz), 3.79-3.65 (m, 2H), 3.57-3.50 (m, 1H), 3.25 (dd, 1H, J ) 10.6, 4.8 Hz), 2.66 (d, 1H, J ) 11.2 Hz), 2.66-2.60 (m, 1H), 2.40 (s, 3H), 1.79 (ddd, 1H, J ) 11.6, 11.6, 11.6 Hz); 13C NMR (100 MHz, CDCl3) δ 147.7 (C), 146.4 (C), 145.6 (C), 143.7 (C), 137.9 (C), 134.9 (C), 133.0 (C), 129.5 (CH), 128.5 (CH), 127.9 (CH), 127.8 (CH), 127.6 (CH), 121.1 (CH), 120.0 (CH), 108.2 (CH), 107.1 (CH), 101.0 (CH2), 72.3 (CH2), 72.2 (CH), 67.4 (CH), 59.0 (CH), 55.8 (CH2), 46.1 (CH), 34.5 (CH2), 21.4 (CH3); MS (EI) m/z 519 (M+, 2), 475 (47), 384 (100), 320 (16), 229 (37); HRMS (EI) m/z calcd for C29H29NO6S 519.1715, found 519.1716; [R]22.3D ) +90.0 (c 1.02, CHCl3). (-)-3-O-Methylpancracine (33). To a solution of 32 (8 mg, 0.021 mmol) in anhydrous dichloromethane (0.3 mL) were added dimethylsulfide (0.023 mL, 0.306 mmol) and BF3 · OEt2 (0.039 mL, 0.306 mmol) at rt. The mixture was stirred for 3 h and quenched with K2CO3 (3 N, 2 mL). The resulting mixture was extracted with dichloromethane (5 mL × 3). The combined extract was washed with brine (15 mL) and dried over K2CO3. Concentration and chromatography on a silica gel column (chloroform/methanol 8:1) gave 33 as a colorless liquid (2.9 mg, 47%). Data for 33: IR (neat) νmax 2849, 1650, 1487, 1222, 937, 731 cm-1; 1H NMR (600 MHz, CDCl3) δ 6.56 (s, 1H), 6.47 (s, 1H), 5.89 and 5.87 (AB quartet, 2H, J ) 1.4 Hz), 5.60 (br s, 1H), 4.45 and 3.92 (AB quartet, 2H, J ) 16.3 Hz), 4.06-4.05 (m, 1H), 3.57-3.56 (m, 1H), 3.51-3.49 (m, 1H), 3.36 (s, 3H), 3.34-3.31 (m, 1H), 3.13 (dd, 1H, J ) 10.9, 1.3 Hz), 2.43 (ddd, 1H, J ) 12.7, 4.9, 3.7 Hz), 2.13 (br s, 1H), 1.71 (dt, 1H, J ) 12.8, 2.8 Hz); 13C NMR (150 MHz, CDCl3) δ 147.2 (C), 146.6 (C), 131.0 (C), 129.7 (C), 122.3 (C), 116.5 (CH), 107.6 (CH), 106.9 (CH), 101.0 (CH2), 80.6 (CH), 66.7 (CH), 59.9 (CH2), 59.6 (CH), 57.1 (CH3), 55.3 (CH2), 45.1 (CH), 27.5 (CH2); MS (EI) m/z 301 (M+, 100), 284 (10), 270 (20), 243 (75), 220 (72), 214 (44), 199 (34), 185 (40), 149 (10), 141 (12), 115 (17), 91 (58), 78 (13), 63 (13); HRMS (EI) m/z calcd for C17H19NO4 301.1314, found 301.1305; [R]26.0D ) -59.8 (c 0.20, CHCl3).

(-)-Manthine (2). To a suspension of NaH (4.9 mg, 0.122 mmol) in anhydrous DMF (0.2 mL) was added a solution of 33 (3.8 mg, 0.012 mmol) in anhydrous DMF (0.2 mL) at 0 °C. The reaction mixture was stirred at rt for 10 min. Iodomethane (0.015 mL, 0.244 mmol) was added. The resulting mixture was stirred for an additional 5 h. Upon cooling to 0 °C, the reaction mixture was quenched with water (0.5 mL) and extracted with dichloromethane (2 mL × 3). The combined extract was washed with brine (5 mL) and dried over Na2SO4. Concentration and chromatography on a silica gel column (chloroform/methanol 40:1) gave 2 as a light yellow solid (3.3 mg, 89%), and recrystallization of 2 in n-hexane gave colorless crystals. Data for 2: mp 113.7-115.5 °C (lit.1,4 114-116 °C); IR (neat) νmax 2851, 1639, 1483, 1235, 1088, 938 cm-1; 1H NMR (500 MHz, CDCl3) δ 6.52 (s, 1H), 6.43 (s, 1H), 5.87 and 5.84 (AB quartet, 2H, J ) 1.5 Hz), 5.54 (br s, 1H), 4.37 and 3.81 (AB quartet, 2H, J ) 16.5 Hz), 3.58 (br s, 1H), 3.52-3.51 (m, 1H), 3.41 (s, 3H), 3.36 (s, 3H), 3.32-3.27 (m, 2H), 3.09-3.01 (m, 2H), 2.31 (ddd, 1H, J ) 13.0, 5.0, 3.5 Hz), 1.42 (dt, 1H, J ) 12.0, 2.5 Hz); 13C NMR (125 MHz, CDCl3) δ 153.6 (C), 146.8 (C), 146.0 (C), 132.1 (C), 124.2 (C), 113.2 (CH), 107.4 (CH), 106.8 (CH), 100.7 (CH2), 77.7 (CH), 76.4 (CH), 60.7 (CH2), 56.8 (CH), 57.4 (CH3), 56.7 (CH3), 55.3 (CH2), 45.6 (CH), 29.1 (CH2); MS (EI) m/z 315 (M+, 44), 300 (9), 284 (26), 257 (52), 229 (36), 197 (21), 155 (34), 141 (70), 128 (100), 115 (62), 91 (24), 77 (19); HRMS (EI) m/z calcd for C18H21NO4 315.1471, found 315.1474; [R]25.9D ) -78.4 (c 0.50, CHCl3; lit.4 [R]25.9D ) -80.0 (c 0.51, CHCl3).

Acknowledgment. National Science Council of the Republic of China (Taiwan) provided financial support. Supporting Information Available: Experimental procedures, detailed spectral characterization data; 1H and 13C NMR spectra of compounds 1, 1a, 2, 7, 9-11, 13-16, 18-21, 25, 27-30, 32, and 33; X-ray data (CIF) for 1a and 9. This material is available free of charge via the Internet at http://pubs.acs.org. JO801089Y

J. Org. Chem. Vol. 73, No. 19, 2008 7585